PROJECT SUMMARY Sickle Cell Disease (SCD) affects over 100,000 individuals in the U.S, mostly from minority ethnicities, leading to significant morbidity and poorer quality of life, often due to recurrent and chronic pain. The time course and mechanisms of transition from recurrent acute pain episodes to chronic pain in SCD represent critical knowledge gaps in the field. A better understanding of the risk factors and mechanisms of transition to chronic pain can facilitate the development of targeted and effective interventions. The candidate and her mentor have developed and established content validity of a web-based electronic pain diary which captures pain on a momentary level, in the patient?s natural environment. These methods also allow the study of fluctuations or intra-individual variability in pain intensity, distinct from pain intensity, as an important facet of the pain experience in SCD. These approaches can now be applied to identify the factors that contribute to the development of chronic pain is SCD patients, as well as to identify the factors that lead to persistence of chronic pain despite cure of SCD by hematopoietic cell transplantation (HCT). HCT provides a unique model for the study of chronic pain where the underlying sickling and vaso-occlusion are removed by HCT. In Aim 1 of this proposal, the candidate will use the framework of two large NIH-sponsored multi-center clinical trials of HCT for SCD to address the relevance of pain variability on patient-reported outcomes (PROs) of physical social and emotional functioning, and in identifying phenotypes of pain. In Aim 2, she will use advanced statistical models and quantitative sensory testing to identify the factors that contribute to pain persistence despite cure of SCD by HCT, the trajectories of pain and PROs, and will identify the patients whose pain is most likely to benefit from HCT. In Aim 3, she will, for the first time, determine the feasibility of a prospective, longitudinal study of the development of chronic pain in SCD. Through this career development award, the candidate will also acquire expertise in advanced statistical methods, gain experience in managing the collection of pain and PRO endpoints in large multicenter trials, and in the design and execution of prospective, longitudinal observational studies of chronic pain in SCD. The candidate is a uniquely qualified and promising early-career clinical investigator in SCD pain research. Her advisory committee consists of experts in SCD (Dr. Lakshmanan Krishnamurti, Dr. Wally Smith, and Dr. Clinton Joiner), HCT for SCD (Dr. Lakshmanan Krishnamurti, and Dr. Edmund Waller), and biostatistical methods for modeling longitudinal diary data (Dr. Courtney McCracken). The Aflac Cancer and Blood Disorders Center, and Emory University provide an outstanding research environment with requisite resources and support for the candidate. The research and training plan will allow the candidate to establish herself as an independent clinical investigator at the unique crossroads of SCD, pain and PRO research, and the use of innovative approaches to advance the field of chronic pain in SCD.